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SHAPE-BASED TWO DIMENSIONAL DESCRIPTOR FOR SEARCHING MOLECULAR DATABASE
HENTABLI HAMZA
“I hereby declare that I have read this thesis and in my opinion this thesis is sufficient in terms of scope and quality for the award of the degree of Master of Science
(Computer Science)”
Signature :
Name : Naomie Salim
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SHAPE-BASED TWO DIMENSIONAL DESCRIPTOR FOR SEARCHING MOLECULAR DATABASE
HENTABLI HAMZA
A thesis submitted in fulfilment of the requirements for the award of the degree of
Master of Science (Computer Science)
Faculty of Computing Universiti Teknologi Malaysia
I declare that this thesis entitled “Shape-Based Two Dimensional Descriptor for Searching Molecular Database” is the result of my own research except as cited in the references. The thesis has not been accepted for any degree and is not concurrently submitted in candidature of any other degree.
Signature :
Name : Hentabli Hamza
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This research study is dedicated to my wife, to my mother, and in the memory of my father
”If we knew what it was we were doing, it would not be called research, would it?” Albert Einstein
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ACKNOWLEDGEMENT
Alhamdulillah, all praises to Allah S.W.T., The Most Greatest and The Most Merciful for His guidance and blessing, because without him I cant finished this research. I also wish to express my gratitude to my thesis supervisor, Prof. Dr. Naomie Salim for her enthusiastic guidance, valuable help, encouragement and patience for all the aspect of the thesis progress. Her numerous comments, criticisms and suggestion during the preparation of this project are greatly appreciated. Also, for her patience on problems that occurred during the process of completing this thesis.
Furthermore, special thanks go to Dr. Faisal Saeed, for many days of scientific discussions, this work would not have been possible without his support. Many thanks goes to the people who supported me in write this thesis, especially amer tawfiq, Dr.Ali ahmed, Dr.Djamel. I also would like to thank all my friends that give me support and help during the writing of the thesis. Their support and help always give me the motivation and energy I need to finish the thesis. My appreciation also extended to all academic and non-academic member of the Faculty of Computing for their warm heart cooperation during my stay in Universiti Teknologi Malaysia.
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ABSTRACT
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ABSTRAK
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TABLE OF CONTENTS
CHAPTER TITLE PAGE
DECLARATION ii
DEDICATION iii
ACKNOWLEDGEMENT iv
ABSTRACT v
ABSTRAK vi
TABLE OF CONTENTS vii
LIST OF TABLES xi
LIST OF FIGURES xiii
1 INTRODUCTION 1
1.1 Introduction 1
1.2 Problem Background 2
1.3 Problem Statement 4
1.4 Research Question 5
1.5 Research Aim 5
1.6 Objectives 6
1.7 Research Scope 6
1.8 Significance and justification of study 7
1.9 Organization of the report 7
1.10 Summary 7
2 LITERATURE REVIEW 8
2.1 Introduction 8
2.2 Chemical Database 9
2.3 Chemical Compounds 9
2.4 Molecular Similarity and Molecular searching 10 2.5 Representation of Chemical Structures 11
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2.5.2 String Representation and Canonical
SMILES 14
2.5.3 Graph Representation 21
2.6 Molecular Representation 22
2.6.1 1D Descriptors 23
2.6.2 2D Descriptors 24
2.6.3 3D descriptors 26
2.7 Searching in Chemical Database 27
2.7.1 Structure Searching 28
2.7.2 Substructure Searching 28
2.7.3 Similarity Searching 29
2.7.4 Molecular Descriptors for Similarity
Searching 31
2.7.5 Similarity Coefficients 32
2.7.5.1 Distance Coefficients 32 2.7.5.2 Association Coefficients 34 2.7.5.3 Correlation Coefficients 36 2.7.5.4 Probabilistic Coefficients 37 2.8 Shape Representation and Description Techniques 37
2.8.1 Classifications of Shape Representation
Techniques 38
2.8.2 Chain Code Representation 39
2.8.3 Syntactic Analysis 41
2.9 Discussion 42
2.10 Summary 45
3 RESEARCH METHODOLOGY 46
3.1 Introduction 46
3.2 Research Design 46
3.3 General Research Framework 47
3.4 Molecular Dataset Preparation 49
3.5 Generating Shape-based Descriptors 54
3.5.1 Language for Writing Descriptors of
Outline Shape of Molecules 54
3.5.2 2D Fingerprint Descriptors of Outline
Shape of Molecules 55
3.5.3 Canonical Representation for Descriptors
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3.6.1 Extended Connectivity Fingerprints
(ECFP) 59
3.6.1.1 Properties of ECFP 59
3.6.1.2 Applications 59
3.6.1.3 Representation and Generation 60 3.6.1.4 The Generation Process 61
3.7 Evaluate the Proposed Descriptors 63
3.7.1 Structure-based approaches 65
3.7.2 Ligand-based approaches 66
3.8 Evaluation Measures of Similarity Performance 69
3.8.1 Tanimoto Coefficient 69
3.8.2 Recall Calculation 70
3.8.3 Kendall rank correlation coefficientτ 71 3.8.4 Basic Local Alignment Search Tool 72
3.9 Summary 75
4 LANGUAGE FOR WRITING DESCRIPTORS OF
OUT-LINE SHAPE OF MOLECULES 76
4.1 Introduction 76
4.2 Materials and Methods 77
4.2.1 Specification Rules 78
4.3 Experimental Design 80
4.4 Validation of the Implemented System 81
4.5 Results and Discussion 85
4.6 Summary 92
5 2D FINGERPRINT DESCRIPTORS OF OUTLINE
SHAPE OF MOLECULES 93
5.1 Introduction 93
5.2 Materials and Methods 95
5.3 Experimental Design 99
5.4 Results and Discussion 105
5.5 Summary 113
6 CANONICAL REPRESENTATIONS FOR
DESCRIP-TORS OF OUTLINE SHAPE OF MOLECULES 114
6.1 Introduction 115
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6.3 Experimental Design 124
6.4 Validation of the implemented System 125
6.5 Results and Discussion 127
6.6 Summary 136
7 CONCLUSION AND FUTURE WORK 137
7.1 Conclusion 137
7.2 Research Contributions 138
7.3 Future Works 139
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LIST OF TABLES
TABLE NO. TITLE PAGE
2.1 Example of SMILES structure of different molecules
illustrating the design rules of SMILES-sturcture. 16 2.2 Examples of descriptors classified according to
dimen-sionality, demonstrated on the saccharin molecule. 23 2.3 Comparison of the three type of searching method in
chemical database 31
2.4 Examples of distance coefficients 34
2.5 Examples of association coefficients 35
2.6 Examples of correlation coefficients 37
3.1 MDDR Activity Classes for DS1 Data Set 53
3.2 MDDR Activity Classes for DS2 Data Set 53
3.3 MDDR Activity Classes for DS3 Data Set 54
3.4 Interpretation of the correlation coefficients size for
positive values. 72
4.1 Validation of the implemented System 82
4.2 Retrieval results of top 1% for data set DS1 86 4.3 Retrieval results of top 5% for data set DS1 87 4.4 Retrieval results of top 1% for data set DS2 87 4.5 Retrieval results of top 5% for data set DS2 88 4.6 Retrieval results of top 1% for data set DS3 88 4.7 Retrieval results of top 5% for data set DS3 89 4.8 Rankings of various types of descriptors Based on
Kendall W Test Results 90
4.9 Numbers of Shaded Cells for Mean Recall of Actives
molecules 91
5.1 List of atoms name that contain two characters and their
new labeling 96
5.2 Sample of Lingo-DOSM descriptor 101
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5.4 Fragmentation of LWDOSM Molecule B 103
5.5 Intermolecular Similarity Calculation for the molecule A
and B 104
5.6 Retrieval results of top 1% for data set DS1 106 5.7 Retrieval results of top 5% for data set DS1 106 5.8 Retrieval results of top 1% and 5% for data set DS1
comparing with LWDOSM 107
5.9 Retrieval results of top 1% for data set DS2 107 5.10 Retrieval results of top 5% for data set DS2 108 5.11 Retrieval results of top 1% and 5 % for data set DS2
comparing with LWDOSM 108
5.12 Retrieval results of top 1% for data set DS3 109 5.13 Retrieval results of top 5% for data set DS3 109 5.14 Retrieval results of top 1% and 5 % for data set DS3
comparing with LWDOSM 110
5.15 Rankings of various types of descriptors Based on
Kendall W Test Results: Top 1% and 5% 111 5.16 Numbers of Shaded Cells for Mean Recall of Actives
Using Different De-scriptors: DS1-DS3 Top 1% and 5% 112
6.1 Validation of the implemented System 125
6.2 Retrieval results of top 1% for data set DS1 129 6.3 Retrieval results of top 5% for data set DS1 129 6.4 Retrieval results of top 1% and 5% for data set DS1
comparing with LWDOSM and Lingo-DOSM 130 6.5 Retrieval results of top 1% for data set DS2 130 6.6 Retrieval results of top 5% for data set DS2 131 6.7 Retrieval results of top 1% and 5% for data set DS2
comparing with LWDOSM and Lingo-DOSM 131 6.8 Retrieval results of top 1% for data set DS3 132 6.9 Retrieval results of top 5% for data set DS3 132 6.10 Retrieval results of top 1% and 5% for data set DS3
comparing DS2 comparing with LWDOSM and
Lingo-DOSM. 133
6.11 Rankings of various types of descriptors based on
Kendall W Test Results 135
6.12 Numbers of Shaded Cells for Mean Recall of Actives
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LIST OF FIGURES
FIGURE NO. TITLE PAGE
2.1 Three main step for molecular descriptor 11
2.2 The chemical structure of aspirin 12
2.3 Fragment code representation for three molecules 13 2.4 Examples of the SMILES Strings for a variety of
molecules 14
2.5 Examples of the Wisswesser Line Notation Strings of
molecule 17
2.6 Examples of the InChI Strings descriptor of molecule 18 2.7 Examples of Canonical versus non-Canonical SMILES 19 2.8 Generation of SMILES: A)Break cycles, B)write as
branches off a main backbone C)spanning tree D) Final
Canonical SMILES. 20
2.9 The connection table for aspirin in the MDL format
(hydrogen-suppressed form), along with its 2D structure 21 2.10 Representations of a molecular structure in 1D, 2D, and
3D. 27
2.11 Classification of shape representation and description
techniques 39
2.12 (a) The directions of the eight connected chain code (K=8). (b) A sample object, a square, and (c) chain code
presentation of the square. 40
2.13 Structural description of chromosome shape 41 3.1 The general research operational framework 48 3.2 Examples of low diversity molecules in MDDR dataset 50 3.3 Examples of high diversity molecules in MDDR dataset 51 3.4 The mean pairwise similarity (MPS) across each set of
active molecules 52
3.5 Framework for generating of Language for Writing
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3.6 2D Fingerprint Descriptors of Outline Shape of
Molecules. 56
3.7 Canonical Representation for Descriptors of Outline
Shape of Molecules. 57
3.8 Generating ALOGP using Pipeline Pilot software. 58
3.9 Molecular Descriptor generation. 58
3.10 Illustration of the effect of iterative updating for a
selected atom in a sample molecule 62
3.11 ECFP generation process 62
3.12 Generation of the fixed-length bit string 63 3.13 Schematic representation of virtual screening
ap-proaches within early-phase drug discovery. 64 3.14 An example workflow for 3D shape-based flexible
alignment: 1) 2D input structures; 2) 3D conformer is generated and the shape is colored by atomic types; 3) the volume intersection, which maximized during the
alignment, is shown along with the resulting pose 65 3.15 Overview of the Ligand Based Virtual Screening
(LBVS) process. (A) Query and database compounds are encoded by pharmacophore patterns or descriptor vectors. (B) Chemical similarity between query and database compounds is quantified. (C) The library compounds are ranked according to their similarity with
the query. 68
3.16 Tanimoto in similarity searching 70
3.17 Generating word seeds. 73
3.18 Examples of how alignment seeds work. Larger word sizes usually mean that there are fewer regions to evaluate (e.g., part a versus part b). Once an alignment is seeded, BLAST extends the alignment according to a threshold (T), which is set by the user. When performing a BLAST query, the computer extends words with a
neighborhood score greater than T (part c). 74 4.1 The external and internal visiting movement in 2D graph 78 4.2 The representation of internal regions (cyclic structures) 79
4.3 The Angle Direction 79
4.4 The disconnect parts representation 80
5.1 LWDOSM calculation process 95
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5.3 LINGO-DOSM fragmentation 99
6.1 The adjacency matrix of the Graph (G) to represented the
aspirin molecule 117
6.2 Example of the Morgan algorithm 119
6.3 Example of canonical enumerations for atoms 121 6.4 Graphical representation of Tree T extracted from aspirin
Molecule. 122
CHAPTER 1
INTRODUCTION
1.1 Introduction
Chemoinformatics is the collection, representation and organization of chemical data to create chemical information in which it can be applied to create chemical knowledge. In pharmaceutical and agrochemical industry, Chemoinformatics has been used for identification of novel compounds with useful and commercially valuable biological properties. The drug discovery process is very complex and it is a multi-disciplinary task with many stages to be performed in a long time. However, the molecule that has the potential to become drugs may cause unexpected long-term side effects and the drug discovery process can take about 12 years and the costs may be up to $350 million per drug [1].
The high costs of bringing a drug into the market have increased the pressure on the pharmaceutical industries. Therefore, attention is given to research and development in order to develop faster and more effective way to produce chemical compounds that can react to the disease and also produce antibodies towards the disease. This has encouraged the study of chemoinformatics and drug discovery as one of the new areas in Malaysia’s research and development (R&D) [1].
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of chemical structure for the property to be represented is an essential task. Molecular descriptors are numerical values (or vectors of numbers) that characterize properties of compounds. They can be generated from a machine-readable structure representation like a 2D connection table or a set of experimental or calculated 3D coordinates. Molecular descriptors should be effective (can differentiate between different compounds) and efficient (fast to calculate) by playing a vital role in similarity calculations especially when a large database is used. However, there is a conflict between these two requirements since the most effective descriptors tend to be the least efficient to calculate, and vice versa. Molecular descriptors can be classified into 1D, 2D and 3D descriptors. Molecule representations based on the real shape of the molecules are important because it represents the physical interaction between molecules, especially protein-ligand bindings, instead most of the descriptors are developed based on the molecule features or topological indices.
1.2 Problem Background
In organic chemistry research the chemists synthesize novel compounds that exhibit the desired properties and perform better than existing compounds. The commercial objective is to sell these new and superior compounds directly or in new products containing them. During the process from the initial creation of a new compound until it is commercialized, a lot of data related to it is generated such as physiochemical properties, analytical and toxicological data. All this data needs to be stored and scientists must be able to search it by chemical structure [2].
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ChemAxon Compound Registration [2] [3] [4] which runs on MySQL. Another issue is that they are closed-source and if such systems are used in the context of scientific experiments, the experiment is not fully reproducable by other scientists unless they also have access to a license for the same system. Because these systems need to be highly configurable, they are also very complex. Configuring and administrating such a system requires a lot of very specific expertise. Consequentially, it can be advantageous to build your own solution especially for organizations that already have an in-house software development department [5, 6, 7]. A custom solution does not have to be highly configurable as it can be tailored to your needs. This includes administrative interfaces for user management and specific tasks like informing all users about new features. Such tools can greatly reduce administrative overhead [2].
The foundation of a chemical information system is the ability to represent molecules in a computer and to compare a molecule’s structure with another. Molecular comparison has been used in the early chemical information systems, e.g. structure and substructure searching [8, 9]. Structure searching involves searching a chemical database for a particular query structure with aims to retrieve all molecules with an exact match to the query structure whereas substructure searching retrieves all molecules that contain the query structure as a subgraph. The equivalence (similarity) between two structures can be achieved by using a graph and subgraph isomorphism algorithms. Isomorphism algorithms are time consuming because it is a combinatorial problem. Various isomorphism algorithms have been developed for efficient performance but they are still too slow for large chemical databases [10, 11, 12, 13], However, structure and substructure searching were later complemented by another searching mechanism called similarity searching.
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similarity methods. Another example of the graph-based similarity methods is the feature trees. The feature trees were introduced by Rarey and Dixon [17], which are the most abstract way of representing a molecule by means of a graph. A feature tree represents hydrophobic fragments and functional groups of the molecule and the way these groups are linked together. Each node in the tree is labelled with a set of features representing chemical properties of the part of the molecule corresponding to the node. The comparison of feature trees is based on matching subtrees of two feature trees onto each other. Feature trees allow similarity searching to be performed against large database, when combined with a fast mapping algorithms [18]. However, the most common similarity approaches use molecules characterized by fingerprints that encode the presence of fragments features in a molecule. The similarity between two molecules is then computed using the number of sub-structural fragments that is common to a pair of structures and a simple association coefficient [19].
1.3 Problem Statement
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additional property information about the molecule [23, 24, 25]. They characterize molecular structures according to their size, degree of branching and overall shape where the structural diagram of molecules is considered as a mathematical graph, but not the contour of molecule shape. In this thesis, we introduced a new shape-based molecular descriptor that have been inspired by research in information retrieval on the use of contour based shape descriptor for image retrieval systems [26, 27, 28]. Shape-based molecular descriptor is a new method to obtain rough description of 2D molecular structure from its 2D outline shape of its 2D diagram. shape-based molecular descriptor is a textual descriptor that allows rigorous structure specification by the use of a very small and natural grammar.
1.4 Research Question
This study will focus on the following questions:
1. How can we develop new descriptor based on 2D shape of molecule to be used in similarity searching?
2. How can this descriptor be modeled to represent the molecule in fingerprint format?
3. How can graph theory be applied to canonical representation of molecule for similarity searching?
1.5 Research Aim
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similarity searching and molecular retrieval.
1.6 Objectives
The objectives of this research are as follows:
1. To develop a new descriptor based on 2D molecular structure shape for similarity searching.
2. To develop a new fingerprint descriptor for shape based representation of chemical compound.
3. To develop canonical representation based on 2D shape of molecule and graph theory for molecular similarity searching.
1.7 Research Scope
In order to achieve the objectives stated above, the scope of this study is limited to the following:
1. Develop the new descriptor based on the shape of molecules extracted from 2D connection table representation.
2. To evaluate the new descriptor and compared with the six standard descriptors (ALOGP, MACCS, EPFP4, CDKFP, PCFP, GRFP), then evaluate using Tanimoto coefficient.
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1.8 Significance and justification of study
The field of molecular descriptors is strongly interdisciplinary and involves a mass of different theories. For the definition of molecular descriptors, knowledge of algebra, graph theory, information theory, computational chemistry, theories of organic reactivity and physical chemistry is usually required. This study is going to produce a descriptor based on shape of molecules, which can be used in similarity searching in chemical database for drug design and discovery.
1.9 Organization of the report
This thesis will be organized into seven Chapters. Chapter 2 will describe the relevant literature review, the fundamentals of chemoinformatics from the molecule descriptors and the molecule searching. Chapter 3 introduces the methodology that is used to build up the proposed descriptor. Chapter 4 introduces the development of the first model labeled as ”Language for Writing Descriptor or Outline Shape of Molecule (LWDOSM)”. The development of the second model 2D Fingerprint Descriptors of Outline Shape of Molecules using the stepwise fragmentation of the first language is presented in Chapter 5 and finally Chapter 6 presents the third and the last model of our work shape-based molecular descriptor SBDM. Chapter 7 discusses and concludes this thesis, highlights the contribution and finding of this work, and provide suggestions and recommendations for future research.
1.10 Summary
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